Sleep-disordered breathing (SDB) is a common condition that affects approximately 5% of all middle-aged and older adults in the general population. It is characterized by recurrent collapse of the upper airway during sleep and is associated intermittent hypoxemia and recurrent arousals. There is an emerging concept in the literature that SDB is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. In spite of the recent advances in understanding these associations, causal links are still not clear. SDB-related intermittent hypoxemia and sleep fragmentation can trigger a cascade of pathophysiologic events including sympathetic nervous system activation, alterations in neuroendocrine function, and release of inflammatory cytokines. However, empirical data on pathways that link SDB to metabolic dysfunction are lacking. The overall objective of current proposal is to examine the mechanisms through which SDB may lead to metabolic abnormalities. To accomplish our goals, we will employ a combination of human and animal experiments to determine whether sleep-related intermittent hypoxia and sleep fragmentation act through different pathways to alter glucose metabolism. We will also determine whether metabolic dysfunction in SDB is reversible with continuous positive airway pressure (CPAP) treatment. Specifically, we propose: 1. To determine the independent and combined effects of sleep-related intermittent hypoxia and sleep fragmentation on metabolic function and characterize mechanisms underlying the metabolic effects. 2. To examine whether treatment of SDB with CPAP improves metabolic function. Specifically, we propose a randomized, sham-controlled clinical trial in subjects with SDB to determine whether CPAP has salutary effects on metabolic function. 3. To investigate, in a murine model, the biologic mechanisms for altered glucose metabolism induced by chronic intermittent hypoxia and sleep fragmentation. The experiments outlined in this application will provide important mechanistic insight into the causal pathways that may link SDB and metabolic dysfunction. The significance of this proposal is that it will help clarify how SDB leads to cardiovascular health outcomes and open therapeutic strategies that could partially curtail the epidemic of insulin resistance, glucose intolerance, and type 2 diabetes mellitus. PUBLIC HEALTH RELEVANCE: Sleep disordered breathing or sleep apnea is a common condition that affects more than 12 million adults in the US and has been associated with daytime sleepiness, memory problems, high blood pressure, cardiovascular disease, and diabetes. The overall objective of this research proposal is to determine how sleep disordered breathing leads to insulin resistance, glucose intolerance, and diabetes. We will also investigate whether treatment of sleep disordered breathing with continuous positive airway pressure improves metabolic function.